Real-world outcomes of brexu-cel in R/R adult ALL

Brexucabtagene autoleucel (brexu-cel) is an autologous, CD19-directed chimeric antigen receptor T-cell therapy that has been approved for the treatment of adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This approval was based on results from the ZUMA-3 trial (NCT02614066), in which brexu-cel demonstrated high complete remission (CR)/CR with incomplete count recovery (CRi), and a median overall survival (OS) of 47 months in responders at the 3-year follow-up.¹

In this article, we summarize four key studies on the real-world outcomes of brexu-cel in adult patients with R/R B-ALL, individually presented by Bezerra,¹ Roloff,² Rabian,³ and Kopmar⁴ at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

Real-world outcomes of brexu-cel in R/R adult B-ALL: Center for International Blood and Marrow Transplant Research registry¹

Real-world outcomes of brexu-cel in adults with R/R B-ALL prospectively enrolled between 2021 and June 23, 2023 in the Center for International Blood and Marrow Transplant Research registry were presented by Bezerra.¹ The outcomes of interest were CR/CRi rates, duration of response, relapse-free survival (RFS), OS, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias.

Results

Of the 230 patients treated, 150 were included in the analysis. Patients had a diverse ethnic background and were heavily pretreated. Based on the baseline characteristics, 90% of the cohort would have been ineligible for the ZUMA-3 trial.

Efficacy

Among the efficacy evaluable patients, the overall CR/CRi rate was 79%, this rate was consistent across age, prior therapies, and the presence of extramedullary disease (EMD) (Figure 1). Among patients who were not in CR/CRi before brexu-cel infusion (n = 96), the CR/CRi rate was 66%.

At a median follow-up of 6.1 months, the 6-month duration of response, RFS, and OS was 72%, 56%, and 79%, respectively; this was consistent across prior therapy and disease status. The rate of subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) among responders was 30%; this was consistent among patients aged <60 years, with and without prior blinatumomab, with and without EMD, with central nervous system (CNS) disease, and those not in CR/CRi after prior therapy.

Safety

Among patients in the safety set, any-grade CRS and Grade ≥3 CRS occurred in 80% and 9%, respectively. Any-grade ICANS and Grade ≥3 ICANS was seen in 47% and 23%, respectively. The median time from onset to resolution for both CRS and ICANS was 6 days, with 50% of patients requiring corticosteroids and 64% requiring tocilizumab. Prolonged cytopenias occurred in 41%, with Grade 4 thrombocytopenia and cytopenia seen in 33% and 31%, respectively. Clinically significant infections occurred in 51%, most of which were bacterial (31%) or viral infections (23%).

Presenter’s conclusion

In this prospective cohort study, brexu-cel demonstrated promising and consistent efficacy across different subgroups with a manageable safety profile consistent with clinical trial settings. Longer follow-up and larger subgroup analyses of this study are currently being planned.

Real-world outcomes of brexu-cel in R/R adult B-ALL: ROCCA²

Data from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA) study was presented by Roloff.² Study endpoints included response and survival rates, toxicities, and predictors of progression-free survival (PFS). Patients treated with brexu-cel who had a minimum of 3 months of follow-up at data cut-off were included.

Results

A total of 189 patients were included in the analysis. Patients were heavily pretreated with a median of four prior lines of therapy and over half had Philadelphia chromosome-negative disease. Based on disease burden, most patients would have been excluded from ZUMA-3.

Toxicity profile

Overall, 157 out of 187 patients experienced any-grade CRS which were mostly Grade 1–2, with only 11% of patients with Grade 3–4 CRS. 105 out of 188 patients had any-grade ICANS, 24% of which were Grade 1–2 and 31% Grade 3–4.

Response and survival

Overall, 90% of patients achieved CR/CRi, most of which were measurable residual disease (MRD)-negative CRs (Figure 2). Of the 35 patients with CNS 2/3 disease status, 12 converted to CNS 1 status without the use of intrathecal bridging therapy, this is due to brexu-cel infusion.

At a median follow-up of 11.4 months, the 6-month and 12-month PFS were 59% and 48%, respectively. With a median PFS of 9.5 months, the 6- and 12-month OS were 78% and 63%, respectively. The median OS was not reached.

In the multivariate analyses, patients aged >60 years, Asians, prior allo-HSCT, and receiving post brexu-cel consolidation/maintenance were significantly associated with a higher PFS. Conversely, prior exposure to inotuzumab ozogamicin (InO) and receipt of bridging therapy was significantly associated with a lower PFS.

In the landmark analysis (n = 157), receiving tyrosine kinase inhibitor maintenance or allo-HSCT after brexu-cel infusion was significantly associated with a higher PFS when compared with those receiving other or no maintenance. Furthermore, the use of consolidation/maintenance strategies in both MRD-negative and MRD-positive patients was significantly associated with a higher PFS.

Presenter’s conclusion

In this ROCCA study, commercial brexu-cel achieved high MRD-negative CRs and promising 1-year PFS and OS rates in adult patients with R/R B-ALL. While rates of high-grade CRS are low, Grade 3–4 ICANS was observed in 31% of patients. This study showed that ages >60 years, prior HSCT, and the use of tyrosine kinase inhibitor or HSCT as maintenance or consolidation are significant predictors of an improved PFS.

Efficacy and tolerance of brexu-cel in R/R adult B-ALL: GRAALL study from DESCAR-T registry³

Real-life data on the efficacy and safety of brexu-cel in adult patients with R/R B-ALL enrolled on the DESCAR-T registry between July 2018 and June 2023 were presented by Rabian.³ The study endpoints included best overall response, OS, and RFS, as well as the grading and incidence of ICANS and CRS.

Results

A total of 66 patients were infused with brexu-cel, and 64 had available response assessment. A third of the patients had Philadelphia chromosome-positive ALL and half of the patients were pretreated with a median of three prior lines of treatment.

Efficacy and safety

At a median follow-up of 13 months, 77% of patients achieved a CR, with 23 out of 25 patients attaining an MRD-negative CR. Older age, prior allo-HSCT, and CRS occurrence were significantly associated with higher CR rates.

In the safety cohort (n = 62), any-grade CRS was seen in 77% (6% Grade >3 CRS). Any-grade ICANS was seen in 45% (8% Grade >3 ICANS).

The median RFS was 12.9 months and the median OS was 15.6 months for all patients. For patients achieving a CR, the median OS was 25.8 months. There was no association between the number of prior lines of therapies, prior InO, prior blinatumomab, or pre-lymphodepletion bone marrow blasts percentage and outcomes; however, patients receiving prior allo-HSCT had a significantly better OS (p = 0.04) and patients with CNS involvement before leukapheresis had a significantly shorter RFS (p = 0.002) and OS (p = 0.008).

Presenter’s conclusion

In this real-world multicenter study, brexu-cel demonstrated promising efficacy and an acceptable safety profile in adult patients with R/R B-ALL. Data from this study suggest that patients with CNS involvement, who would have been ineligible for ZUMA-3, have limited benefit with brexu-cel when compared with other patients.

Real-world toxicity profile of brexu-cel in R/R adult B-ALL: ROCCA⁴

The toxicity profile of brexu-cel in adults with R/R B-ALL from the ROCCA multicenter study was presented by Kopmar.⁴ The outcomes of interest were CRS, ICANS, and other toxicities. Patients who received U.S Food and Drug Administration (FDA) approved brexu-cel between October, 2021 until June 30, 2023, across 25 centers in the US and had at least 3 months of follow-up were included in this analysis.

Results

A total of 152 patients were evaluated for response, the majority of whom received a median of four prior lines of therapy, and 51% with ≥5% blasts at apheresis.

Incidence of CRS and ICANS

Any-grade CRS occurred in 82% of patients (9% of patients experienced Grade 3+ CRS). Any-grade ICANS was seen in 56% of patients (Grade 3+ ICANS occurred in 31%). A total of 133 patients developed CRS and/or ICANS. The rates of any-grade CRS/ICANS and Grade 3+ ICANS were similar between ROCCA and ZUMA-3, but the rates of severe CRS were significantly lower in ROCCA (Figure 3).

Overall, 68% of patients received tocilizumab for the treatment of CRS/ICANS; 31% of these patients responded and 9% were tocilizumab-refractory. Of the 61% of patients who received corticosteroids, 37% responded to the first steroid trial and 10% were steroid refractory. 21% of the study cohort received anakinra and 4% of patients received other agents for the management of CRS/ICANS.

Univariate analyses revealed a significant association between active disease (≥5% marrow blasts and/or EMD) and Grade 3+ ICANS (p = 0.008). The Cox aggression analysis showed a significant association between Grade 3+ CRS and death (p = 0.05).

Incidence of other toxicities

Hemophagocytic lymphohistiocytosis was reported in 6 patients which overlapped with infections or occurred after CRS/ICANS. The most common infections that occurred between Day 0 and Day 28 were bacterial (n = 12), fungal (n = 6), pneumonia (n = 3), and cytomegalovirus (n = 4). A total of 9 deaths occurred by Day 28 of the study due to CRS (n = 3), ICANS (n = 3), infections (n = 5), disease progression (n = 2), and hemophagocytic lymphohistiocytosis (n = 1).

Presenter’s conclusion

This real-world study reported similar rates of severe ICANS, but a lower incidence of severe CRS compared to ZUMA-3. Severe ICANS was significantly associated with active disease, and severe CRS was associated with a higher risk of death.